RESUMEN
BACKGROUND: Single-nucleotide polymorphism (SNP) haplotype and SNP-SNP interactions of CTLA-4 and CD40 genes, with susceptibility to Graves' disease (GD), were explored in a Chinese Han population. METHODS: SNP were genotyped by high resolution melting (HRM). Use the method of Pearson χ2 test and Logistic regression for the association between single SNP and Graves' disease. Using the method of χ2 test and Multifactor Dimensionality Reduction (MDR) to analysis the haplotype frequency distribution, the interaction of SNPs respectively. RESULTS: Genotypic and allelic frequencies of SNP rs231775, rs3087243 and rs1883832 were statistically different between controls and GD (p < 0.05). Mutant allelic frequency of G rs231775 was higher, and A and T allelic frequencies of rs3087243 and rs1883832 were lower in GD than in controls (P < 0.05). In CTLA-4 rs1024161, rs5742909, rs231775, rs231777, rs231779, rs3087243 and rs11571319 showed D' < 50% and r2 < 0.3 among each SNP. We identified six commonly found haplotypes; TCGCTGC was associated with the highest GD risk (OR = 2.565) and TCACTAC the lowest (OR = 0.096). MDR analysis indicated interactions among the rs231775 GG, rs231779 TT and rs3087243 GG genotypes in CTLA-4 might increase GD risk by 2.53-fold (OR = 2.53). CONCLUSION: CTLA-4 and CD40 were associated with GD incidence in a Chinese Han population. The TCGCTGC and TCACTAC haplotypes in the CTLA-4 gene, were risk and protective factors for Graves'disease respectively. Interactions among the SNPs of rs231775, rs231779 and rs3087243 significantly increase the susceptibility to GD.
Asunto(s)
Antígenos CD40/genética , Antígeno CTLA-4/genética , Epistasis Genética , Predisposición Genética a la Enfermedad , Enfermedad de Graves/genética , Polimorfismo de Nucleótido Simple , Adulto , Alelos , Pueblo Asiatico , Antígenos CD40/metabolismo , Antígeno CTLA-4/metabolismo , Estudios de Casos y Controles , Femenino , Expresión Génica , Frecuencia de los Genes , Enfermedad de Graves/etnología , Enfermedad de Graves/metabolismo , Enfermedad de Graves/patología , Haplotipos , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Reducción de Dimensionalidad Multifactorial , RiesgoRESUMEN
The aim of this study was to investigate whether a genetic combined effect exists between CD40-1C>T and CTLA-4+6230G>A (CT60) polymorphisms and whether the combined effect renders susceptibility to Graves' disease (GD). We recruited 260 patients with GD and 248 healthy controls. Single nucleotide polymorphisms were genotyped by polymerase chain reaction-high resolution melting. Genetic polymorphisms related to GD were identified, levels of thyroid stimulating hormone receptor antibodies (TRAb) were measured, and genetic interactions were assessed by logistic regression analysis. Significant difference in allele and genotype frequency of CD40-1C>T polymorphism was observed between the patients and control subjects (P<0.001, 0.002 respectively). As for CTLA-4+6230G>A polymorphism, significant difference was observed only in allele frequencies between the patient and control groups (P=0.014). Moreover, a significant combined effect was presented in CD40-1C>T and CTLA-4+6230G>A polymorphism (P=0.020), and all, but one, combination CC-genotype of CD40-1C>T and GG-genotype of CTLA-4+6230G>A polymorphism has 54% lower risk of GD development than subjects with the CC and GG genotypes (OR=0.46, 95% CI=0.25-0.84). In newly onset GD group, neither single SNP (CD40-1C>T or CTLA-4+6230G>A polymorphism) nor their combined effect was showed a significant association with TRAb concentration (all P>0.05). Our findings suggest a possible additive combined effect between CD40-1C>T and CTLA4+6230G>A polymorphisms in the development of GD.